The proposed Midcareer Investigator Award is designed to provide the candidate with salary support to devote more time to patient- oriented research and to facilitate his role in mentoring beginning clinical investigators in the field of functional brain imaging in neurodegenerative disorders. Research plan: Parkinson's disease (PD) is the most common degenerative hypokinetic movement disorder. Great strides have been made in the understanding of the pathophysiological mechanisms underlying the neurodegenerative processes in PD, prompting clinical trials of new therapies aimed at slowing or halting the progression of these diseases. To assess these new therapies, reliable in vivo markers of neuronal loss are needed. Currently available clinical measures of disease progression are relatively insensitive, and may not accurately reflect the extent of neuropathological change. Alternatively, quantitative biologically relevant brain imaging markers now exist which may be suitable as outcome measures for clinical trials. Specifically, we have developed three novel methods of assessing disease progression using positron emission tomography (PET): (1) The quantification of dopaminergic function using a radioligand which binds selectively to the dopamine transporter (DAT); (2) The quantification of metabolic brain networks in the resting state; and (3) The quantification of dynamic changes in brain-behavior relationships using regional blood flow activation and network analysis. The goal of the proposed project is to assess the extent to which neurochemical and functional PET imaging markers are sensitive to change in early stage PD, and to compare these measures to standard clinical indices of disease progression. To this end, we propose a longitudinal five-year study to assess disease progression using neurochemical, metabolic, and functional activation PET markers. We hypothesize that PET measures will be more sensitive to disease progression than clinical measures. If this is the case, clinical trials designed to assess potential neuroprotective therapies could require fewer patients and be completed in less time. Mentoring plan: The candidate will recruit promising young physicians who have completed high level clinical training in neurology and ancillary specialties. He will afford these individuals with a stimulating post-graduate experience involving specialized aspects of patient-oriented research in movement disorders. He will also provide structured training in the fundamentals of experimental neurological research in using new functional brain imaging techniques.